WO2001047866A1 - Substituierte 1- und 2-naphthol-mannichbasen - Google Patents
Substituierte 1- und 2-naphthol-mannichbasen Download PDFInfo
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- WO2001047866A1 WO2001047866A1 PCT/EP2000/012972 EP0012972W WO0147866A1 WO 2001047866 A1 WO2001047866 A1 WO 2001047866A1 EP 0012972 W EP0012972 W EP 0012972W WO 0147866 A1 WO0147866 A1 WO 0147866A1
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- 0 C*N(*)C(*)N(C)* Chemical compound C*N(*)C(*)N(C)* 0.000 description 1
- BPTYXJLTLRHOPE-UHFFFAOYSA-N CN(C)C(c1ccccc1)c(c(ccc(OC)c1)c1cc1C(ON)=O)c1O Chemical compound CN(C)C(c1ccccc1)c(c(ccc(OC)c1)c1cc1C(ON)=O)c1O BPTYXJLTLRHOPE-UHFFFAOYSA-N 0.000 description 1
- FFLJXBMXQPKLQM-UHFFFAOYSA-N COc(cccc1C(c(ccc2c3cccc2N)c3O)N2CCOCC2)c1OC Chemical compound COc(cccc1C(c(ccc2c3cccc2N)c3O)N2CCOCC2)c1OC FFLJXBMXQPKLQM-UHFFFAOYSA-N 0.000 description 1
- YLFZQJHKPQDBQJ-UHFFFAOYSA-N COc(cccc1C(c2cc(Cl)c(cccc3)c3c2O)N2CCOCC2)c1OC Chemical compound COc(cccc1C(c2cc(Cl)c(cccc3)c3c2O)N2CCOCC2)c1OC YLFZQJHKPQDBQJ-UHFFFAOYSA-N 0.000 description 1
- UXSPYSBABJMNPJ-UHFFFAOYSA-N Cc1ccccc1C(c1cc(Cl)c(cccc2)c2c1O)N1CCCCC1 Chemical compound Cc1ccccc1C(c1cc(Cl)c(cccc2)c2c1O)N1CCCCC1 UXSPYSBABJMNPJ-UHFFFAOYSA-N 0.000 description 1
- KYASZMQKBPEULN-UHFFFAOYSA-N Nc1cccc2c1ccc(C(c1ccccc1Cl)N1CCCCC1)c2O Chemical compound Nc1cccc2c1ccc(C(c1ccccc1Cl)N1CCCCC1)c2O KYASZMQKBPEULN-UHFFFAOYSA-N 0.000 description 1
- WESLOKYESXZJSF-UHFFFAOYSA-N Oc1c(C(c2ccccc2)N2CCOCC2)c(cccc2)c2cc1 Chemical compound Oc1c(C(c2ccccc2)N2CCOCC2)c(cccc2)c2cc1 WESLOKYESXZJSF-UHFFFAOYSA-N 0.000 description 1
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C07C237/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system of the same carbon skeleton
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- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Definitions
- the invention relates to substituted 1- and 2-naphthol Mannich bases, processes for their preparation, medicaments containing these compounds and the use of these compounds for the production of medicaments.
- Classic opioids such as the morphine
- morphine are effective in the treatment of severe to very severe pain.
- undesirable side effects include respiratory depression, vomiting, sedation, constipation and a development of tolerance.
- the object of the present invention was therefore to provide new compounds which are particularly suitable as active ingredients in pharmaceuticals. These active ingredients are intended in particular for pain therapy and for the treatment of inflammatory and allergic reactions, drug and / or alcohol abuse, diarrhea, gastritis, UIcera, cardiovascular diseases, urinary incontinence, depression, shock conditions, migraines, narcolepsy, overweight, asthma, glaucoma and / or hyperkinetic syndrome.
- this object is achieved by the provision of substituted 1- and 2-naphthol Mannich bases of the general formula I below, which have a pronounced analgesic effect and which are also suitable for the treatment of inflammatory and allergic reactions, drug and / or alcohol abuse, diarrhea , Gastritis, ulcer, cardiovascular disease, urinary incontinence, depression, shock, migraine, narcolepsy, obesity, asthma, glaucoma and / or hyperkinetic syndrome.
- the invention therefore relates to substituted 1- and 2-naphthol Mannich bases of the general formula I,
- R 9 is an aryl radical, a heteroaryl radical or an alkyl radical without an acidic proton in the ⁇ -position, preferably an unsubstituted phenyl radical or at least one with C- -alkyl-, C ⁇ -3 -alkoxy-, halogen- , CF 3 -, CN, O-phenyl or OH substituted phenyl radical, particularly preferably an unsubstituted phenyl radical or a 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2 -Methyl-phenyl-, 3-methyl-phenyl-, 4-methyl-phenyl-, 2-tert-butyl-phenyl-, 3-tert-butyl-phenyl-, 4-tert-butyl-phenyl-, 2-fluoro -phenyl-, 3-fluorophenyl-, 4-fluorophenyl-, 2-chlorophenyl-
- R 10 , R 11 the same or different, a branched, unbranched, saturated, unsaturated, unsubstituted or at least monosubstituted -6 alkyl radical or an unsubstituted or at least monosubstituted phenyl, benzyl or phenethyl radical, preferably is a saturated, unsubstituted or at least monosubstituted C1-6 alkyl radical, particularly preferably a CH 3 radical,
- R 14 H, a Ci.io-alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C 1-6 alkylene group, preferably a C 1-6 alkyl or one means an aryl radical bonded via a C 2 alkylene group,
- R 15 H, a C ⁇ - 10 alkyl, an aryl, a heteroaryl or an aryl bound via a C- ⁇ - 6 alkylene group or heteroaryl residue, preferably a C ⁇ -6 alkyl or an over is a C 2 alkylene group bound aryl radical,
- R 16 H, CO (R 17 ), a Ci.io-alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C 6 alkylene group, preferably H, a C 6 Alkyl, an aryl radical bonded via a C 2 alkylene group or CO (R 17 ), particularly preferably H or CO (R 17 ),
- R 17 H, a Ci.io-alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C 6 alkylene group, preferably one C ⁇ _6-alkyl, one via a C ⁇ . 2 -alkylene group bound aryl radical or an optionally with F-, Cl-, Br-, C ⁇ . 3- alkoxy-substituted phenyl radical, particularly preferably a phenyl radical which is optionally substituted by F-, Cl-, Br-, Ci ⁇ - alkyl, -C-3-alkoxy,
- R H, a Ci.io-alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C 6 alkylene group, preferably a C 6 alkyl, one via a C 1. 2 -alkylene group-bonded aryl radical or an optionally with F-, Cl-, Br-, -C 4 alkyl, or -C. 3 -alkoxy-substituted phenyl or naphthyl radical, particularly preferably a phenyl radical optionally substituted with F-, Cl-, Br-, -C-4-alkyl, -C ⁇ -3-alkoxy,
- R 20 H, a C 10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C 6 alkylene group, preferably H, a C 1. 6 -alkyl, an aryl radical bonded via a C 2 alkylene group or a phenyl radical optionally substituted with F, Cl, Br, C 1 -C 4 alkyl, or C 3 alkoxy, particularly preferably H or an optionally with F-, Cl-, Br-, -CC 4-alkyl, -C. 3 -alkoxy- substituted phenyl radical means
- R 22 H, NHNH 2 , NHR 18 , a C ⁇ . 10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C 6 alkylene group, preferably H, a C 1. 6 alkyl, an aryl radical bonded via a C 2 alkylene group, NHNH 2 , NHR 18 or an optionally with F, Cl, Br, or C ⁇ - 3 alkoxy-substituted phenyl radical, particularly preferably NHNH 2 , NHR 18 or one optionally with F-, Cl-, Br-, C ⁇ -4-alkyl, or C ⁇ .
- 3 -alkoxy-substituted phenyl radical very particularly preferably NHNH 2 or NHR 18 and / or their racemates, enantiomers, diastereomers and / or corresponding bases and / or corresponding salts of physiologically tolerated acids,
- radicals R 3 to R 8 and R 12 H
- radicals R 3 to R 8 and R 12 H
- radical R 9 phenyl, 4-methoxyphenyl, 4-dimethylaminophenyl-, 4-hydroxy-2,3-di-tert-butylphenyl, 2,3-dihydrobenzodioxane, 4 -Nitrophenyl- or benzo-1, 3-dioxole
- radicals R 10 and R 11 together (CH 2 ) 2 0 (CH 2 ) 2 mean
- radicals R 3 to R 8 and R 12 H
- radical R 9 phenyl
- radicals R 3 to R 8 and R 12 H
- radical R 9 4-methoxyphenyl or benzo-1, 3-dioxole
- radicals R 3 to R 8 and R 12 H
- radical R 9 phenyl
- radicals R 3 to R 8 and R 12 H
- radical R 9 phenyl or 4-methoxyphenyl
- radicals R 10 and R 11 together (CH 2 ) 5 as hydrochloride
- radicals R 3 to R 8 H
- radical R 12 CH 3
- radical R 9 thiophene, 4-methoxyphenyl or 3,4-dimethoxyphenyl
- Phenyl, R 10 and R 11 together (CH 2 ) 5 mean
- R 3 to R 8 and R 12 H
- the radical R 9 phenyl, 2-bromophenyl, 3-bromophenyl or 4-bromophenyl
- the radicals R 10 and R 11 together (CH 2 ) 5
- R 3 to R 6 , R 8 , R 12 H
- the radical R 7 CH 3
- the radical R 9 4-methoxyphenyl or phenyl
- the radicals R 10 , R 11 together (CH 2 ) 5
- R 3 to R 8 and R 12 H
- the radical R 9 phenyl
- the radical R 10 CH 3
- Alkyl radicals are preferably understood to mean at least one hydrocarbon radical which is substituted at least once with halogen, CN, CF 3 - and / or OH, particularly preferably with F, Cl, Br or OH. If these contain more than one substituent, these substituents can be the same or different.
- the alkyl radicals can be branched, unbranched or cyclic.
- alkyl radicals methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl are particularly preferred , Heptyl, nonyl or decanyl.
- An aryl residue is preferably at least one, with an OH, a halogen, preferably F, Br or Cl, a CF 3 , a CN, a d- ⁇ -alkyl, a C 6 alkoxy or a phenyl radical which is substituted by phenyl or naphthyl radicals.
- a halogen preferably F, Br or Cl
- a CF 3 a CN
- a d- ⁇ -alkyl a C 6 alkoxy or a phenyl radical which is substituted by phenyl or naphthyl radicals.
- the unsubstituted or substituted phenyl radicals can also be fused with further rings.
- a heteroaryl radical is understood to mean aromatic compounds which have at least one heteroatom, preferably nitrogen and / or oxygen and / or sulfur, particularly preferably nitrogen and / or oxygen and which preferably have a halogen, a CN or a CF 3 - or OH radical may be substituted.
- the heteroaryl radical is very particularly preferably one with a substituted or unsubstituted thiophene, pyrrolyl or furfuryl radical.
- substituted 1- and 2-naphthol Mannich bases are particularly preferred:
- the invention further relates to processes for the preparation of substituted 1- and 2-naphthol Mannich bases of the general formula I in which the radical R 12 is H and the radicals R 1 to R 11 , the radicals R 13 to R 18 and the radicals R 20 to R 22 have the meaning according to the general formula I, which are characterized in that
- R 9 has the meaning according to general formula I, in solution, preferably in an organic solvent, particularly preferably in toluene, in the presence of a base, preferably potassium carbonate or
- radicals R 10 and R 11 have the meaning according to the general formula I, to amino compounds of the general formula IV
- R 9 has the meaning according to general formula I, in solution, preferably in an organic solvent, particularly preferably in toluene, in the presence of a base, preferably potassium carbonate or
- 2 -alkylene group-bound aryl radical and the radicals R 1 to R 11 , R 13 to R 18 and R 20 to R 22 have the meaning according to the general formula I, by filtration, preferably by filtration through a scavenger resin , particularly preferably by filtration over polymer-bound tris (2-aminoethyl) amine (Novabiochem, Bad Soden) and / or 3- (3-mercaptophenyl) propanamidomethyl polystyrene (Argonaut, Muttenz, Switzerland).
- the substituted 1- and 2-naphthol Mannich bases according to the invention are preferably synthesized on an automatic plant from Zymark according to FIG. 1 and FIG. 2 as described below.
- substituted 1- and 2-naphthol-Mannich bases of the general formula I according to the invention can be prepared with physiologically compatible acids, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid,
- Salt formation is preferred carried out in a solvent, particularly preferably in diethyl ether, diisopropyl ether, alkyl acetate, preferably ethyl acetate, acetone and / or 2-butanone. Salt formation with trimethylchlorosilane in methyl ethyl ketone is very particularly preferred.
- the substituted 1- and 2-naphthol-Mannich bases of the general formula I according to the invention are toxicologically harmless and are therefore suitable active pharmaceutical ingredients.
- the invention therefore furthermore also relates to medicaments which contain at least one substituted 1- and / or 2-naphthol-Mannich base of the general formula I and optionally further active substances and / or auxiliaries as active substance.
- the medicament can preferably also contain a mixture of enantiomers of at least one substituted 1-naphthol Mannich base and / or 2-naphthol Mannich base of the general formula I, the mixture preferably not having the enantiomers in equimolar amounts.
- the relative proportion of one of the enantiomers is particularly preferably 5 to 45 mol%, very particularly preferably 10 to 40 mol%, based on the total mixture of the enantiomers.
- the medicaments are preferably used for the treatment / control of pain and / or inflammatory reactions and / or allergic reactions and / or drug abuse and / or alcohol abuse and / or diarrhea and / or gastritis and / or UIcera and / or cardiovascular diseases and / or urinary incontinence and / or depression and / or shock states and / or migraines and / or narcolepsy and / or overweight and / or asthma and / or glaucoma and / or hyperkinetic syndrome.
- carrier materials In addition to at least one substituted 1- and / or 2-naphthol Mannich base of the general formula I, carrier materials, fillers, solvents, diluents, dyes and / or binders are used to prepare corresponding pharmaceutical formulations.
- carrier materials In addition to at least one substituted 1- and / or 2-naphthol Mannich base of the general formula I, carrier materials, fillers, solvents, diluents, dyes and / or binders are used to prepare corresponding pharmaceutical formulations.
- excipients depends on whether the drug is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally, for example for infections of the skin, mucous membranes and eyes.
- compositions in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
- the substituted 1 or. 2-Naphthol-Mannich bases of the general formula I in a depot in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration, are suitable percutaneous application preparations.
- the compounds of the general formula I according to the invention can be released with a delay from oral or percutaneous preparation forms become.
- the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease.
- the effect of the 1- and 2-naphthol Mannich bases according to the invention is determined in particular by the affinity for the N-methyl-D-aspartate (NMDA) receptor family, for ⁇ -adrenergic receptors and opioid receptors.
- NMDA N-methyl-D-aspartate
- mice Male NMRI mice weighing 25-30 g were used for this. Groups of 10 animals per substance dose received 0.3 ml / mouse 10 minutes after intravenous administration of the test substances of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, from Sigma, Deisenhofen; preparation of the solution with addition of 5% ethanol and storage applied intraperitoneally in a water bath at 45 ° C). The animals were placed individually in observation cages.
- phenylquinone phenylbenzoquinone
- a capper station for closing the reaction tubes
- a robot 1 for closing the reaction tubes
- a robot 2 for closing the reaction tubes
- the robot 1 moving the reaction tubes or the corresponding racks and the Robot 2
- pipettes the reagents into the reaction tubes a temperature-controlled reactor block (section 4)
- stirring blocks section 5
- a filtration station section 6 in which the reaction solution is filtered off.
- Figure 2 also includes a robot 1 (Section 1) and a robot 2 (Section 2), both of which are the glass tubes with the synthesis products on the different Move stations.
- the stations are specifically a vortexer (Section 3) for mixing the samples and for metering in solutions or solvents, a spin reactor (Section 4) for mixing samples and a phase detection station (Section 5) Detection of the phase boundary and phase separation as well as a station (section 6) for drying the synthesis products over salt cartridges.
- a round-bottom tube made of glass (diameter 16 mm, length 125 mm) with a thread was provided manually with a stirrer and closed on the capper station (item 1) according to FIG. 1 with a screw cap with a septum.
- Robot 1 placed the tube in the reactor block (Section 4) heated to 25 ° C.
- Robot 2 (item 3) added the following reagents in succession:
- the iminium salts were previously prepared as indicated in the examples below.
- the reaction mixture was then stirred at 90 ° C. in one of the stirring blocks (item 5) for 960 minutes.
- the reaction solution was then filtered off at the filtration station (Section 6).
- the tube was rinsed twice with 1 ml dichloromethane and 200 ⁇ l water.
- the rack with the tubes was then placed manually on an automatic processing system according to FIG. 2. There, the reaction mixture was mixed on a vortexer (Section 3) with 2 ml of water and 2 ml of ethyl acetate.
- the mixture was adjusted to a pH value of 1 with 1 ml of aqueous 5% hydrochloric acid solution.
- the aqueous phase was mixed again with 1.5 ml of ethyl acetate.
- the solution was shaken, centrifuged and the organic phase was pipetted off.
- the combined organic phases were dried over 2.4 g of MgSO 4 (granulated). The solvent was removed in a vacuum centrifuge.
- the preparation was carried out in accordance with general synthesis instructions 4 from 5-hydroxy-1-naphthalenesulfonamide and benzylidene-dimethyl-ammonium chloride.
- Phenyl 4- (dimethylaminophenylmethyl) -3-hydroxy-naphthalene-2-carboxylate The preparation was carried out in accordance with general synthesis instructions 4 from phenyl 2-hydroxy-3-naphthoate and benzylidene-dimethylammonium chloride, which had been prepared according to Example 1.
- the preparation was carried out according to general synthesis instructions 4 from 4- (2,3-dimethoxybenzylidene) morpholin-4-ium chloride and 4-chloro-1-naphthol.
- the preparation was carried out in accordance with general synthesis instructions 4 and 5 from 1-naphthol and benzylidene-dimethyl-ammonium chloride and 4-methoxybenzyl chloride.
- the preparation was carried out according to general synthesis instructions 4 and 5 from 2-naphthol, benzylidene-dimethyl-ammonium chloride and 4-methoxybenzyl chloride.
- the preparation was carried out according to the general synthesis instructions 4 and 6 from 2-naphthol, benzylidene-dimethyl-ammonium chloride and 2-chlorobenzoyl chloride.
- 2nd stage 1- (phenylpiperidin-1-yl-methyl) -naphthalin-2-ol
- the preparation was carried out according to general synthesis instructions 4 from 1-benzylidene-piperidinium chloride and 2-naphthol.
- Phenylquinone-induced writhing was performed on the mouse as described above.
- the investigated compounds according to the invention showed an analgesic effect.
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Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT00990799T ATE294773T1 (de) | 1999-12-27 | 2000-12-20 | Substituierte 1- und 2-naphthol-mannichbasen |
JP2001549340A JP2003519115A (ja) | 1999-12-27 | 2000-12-20 | 置換1−および2−ナフトールマンニッヒ塩基 |
DK00990799T DK1246790T3 (da) | 1999-12-27 | 2000-12-20 | Substituerede 1- og 2-naphthol-Mannichbaser |
AU30147/01A AU775709B2 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
SK853-2002A SK8532002A3 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol Mannich bases |
EP00990799A EP1246790B1 (de) | 1999-12-27 | 2000-12-20 | Substituierte 1- und 2-naphthol-mannichbasen |
CA002394098A CA2394098A1 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
MXPA02005865A MXPA02005865A (es) | 1999-12-27 | 2000-12-20 | Bases de mannich sustituidas con 1- y 2-naftol. |
PL00356523A PL356523A1 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
US10/149,449 US6774136B2 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
SI200030722T SI1246790T1 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
HU0203732A HUP0203732A3 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
NZ519976A NZ519976A (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
BR0016781-9A BR0016781A (pt) | 1999-12-27 | 2000-12-20 | Bases de 1-naftol e 2-naftol - mannich substituìdas |
KR1020027007536A KR20020062334A (ko) | 1999-12-27 | 2000-12-20 | 치환된 1- 및 2-나프톨 만니히 염기 |
DE50010253T DE50010253D1 (de) | 1999-12-27 | 2000-12-20 | Substituierte 1- und 2-naphthol-mannichbasen |
IL149920A IL149920A (en) | 1999-12-27 | 2002-05-29 | 1 and 2 Twists are transformed into basic manikins, processes for their preparation and their use for the preparation of drugs |
NO20022896A NO20022896L (no) | 1999-12-27 | 2002-06-17 | Substituerte 1- og 2-naftol mannich baser |
HK03102524A HK1051845A1 (en) | 1999-12-27 | 2003-04-09 | Substituted 1 and 2 naphthol mannich bases |
US10/757,581 US7202242B2 (en) | 1999-12-27 | 2004-01-15 | Substituted 1 and 2-naphthol Mannich bases |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19963179A DE19963179B4 (de) | 1999-12-27 | 1999-12-27 | Substituierte 1- und 2-Naphthol-Mannichbasen |
DE19963179.4 | 1999-12-27 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/149,449 A-371-Of-International US6774136B2 (en) | 1999-12-27 | 2000-12-20 | Substituted 1 and 2 naphthol mannich bases |
US10149449 A-371-Of-International | 2000-12-20 | ||
US10/757,581 Division US7202242B2 (en) | 1999-12-27 | 2004-01-15 | Substituted 1 and 2-naphthol Mannich bases |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001047866A1 true WO2001047866A1 (de) | 2001-07-05 |
WO2001047866A9 WO2001047866A9 (de) | 2002-11-07 |
Family
ID=7934623
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/012972 WO2001047866A1 (de) | 1999-12-27 | 2000-12-20 | Substituierte 1- und 2-naphthol-mannichbasen |
Country Status (28)
Country | Link |
---|---|
US (2) | US6774136B2 (zh) |
EP (1) | EP1246790B1 (zh) |
JP (1) | JP2003519115A (zh) |
KR (1) | KR20020062334A (zh) |
CN (1) | CN1247523C (zh) |
AT (1) | ATE294773T1 (zh) |
AU (1) | AU775709B2 (zh) |
BR (1) | BR0016781A (zh) |
CA (1) | CA2394098A1 (zh) |
CO (1) | CO5251380A1 (zh) |
CZ (1) | CZ20022240A3 (zh) |
DE (2) | DE19963179B4 (zh) |
DK (1) | DK1246790T3 (zh) |
ES (1) | ES2241688T3 (zh) |
HK (1) | HK1051845A1 (zh) |
HU (1) | HUP0203732A3 (zh) |
IL (1) | IL149920A (zh) |
MX (1) | MXPA02005865A (zh) |
NO (1) | NO20022896L (zh) |
NZ (1) | NZ519976A (zh) |
PE (1) | PE20010986A1 (zh) |
PL (1) | PL356523A1 (zh) |
PT (1) | PT1246790E (zh) |
RU (1) | RU2002120479A (zh) |
SK (1) | SK8532002A3 (zh) |
UY (1) | UY26507A1 (zh) |
WO (1) | WO2001047866A1 (zh) |
ZA (1) | ZA200204289B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7964732B2 (en) | 2006-11-17 | 2011-06-21 | Pfizer Inc. | Substituted bicyclocarboxyamide compounds |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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DE102005033732B4 (de) | 2005-05-27 | 2014-02-13 | Grünenthal GmbH | Trennung stereoisomerer N,N-Dialkylamino-2-alkyl-3-hydroxy-3-phenyl-alkane |
EP2891649B1 (en) * | 2010-02-17 | 2018-04-11 | Cornell University | Prolylhydroxylase inhibitors and methods of use |
WO2011149801A1 (en) * | 2010-05-28 | 2011-12-01 | Merck Sharp & Dohme Corp. | Naphthalene carboxamide m1 receptor positive allosteric modulators |
CN103193676B (zh) * | 2013-04-18 | 2014-03-19 | 安徽工业大学 | 一锅法合成1-氨甲酸酯基烷基-2-萘酚的方法 |
CN103664826B (zh) * | 2014-01-07 | 2016-06-29 | 西北师范大学 | 一种氨基萘酚类化合物的制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996022276A1 (fr) * | 1995-01-20 | 1996-07-25 | Nippon Shinyaku Co., Ltd. | Derives d'ethylamine et medicaments |
EP0864559A1 (de) * | 1997-03-14 | 1998-09-16 | Grünenthal GmbH | Substituierte Aminoverbindungen und ihre Verwendung als analgetisch wirksame Substanzen |
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CN1268135A (zh) * | 1997-06-23 | 2000-09-27 | 吉富制药株式会社 | 螺杆菌属感染引起的疾病的预防/治疗剂 |
-
1999
- 1999-12-27 DE DE19963179A patent/DE19963179B4/de not_active Expired - Fee Related
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2000
- 2000-12-20 SK SK853-2002A patent/SK8532002A3/sk unknown
- 2000-12-20 CA CA002394098A patent/CA2394098A1/en not_active Abandoned
- 2000-12-20 ES ES00990799T patent/ES2241688T3/es not_active Expired - Lifetime
- 2000-12-20 EP EP00990799A patent/EP1246790B1/de not_active Expired - Lifetime
- 2000-12-20 DE DE50010253T patent/DE50010253D1/de not_active Expired - Lifetime
- 2000-12-20 WO PCT/EP2000/012972 patent/WO2001047866A1/de active Search and Examination
- 2000-12-20 RU RU2002120479/04A patent/RU2002120479A/ru unknown
- 2000-12-20 KR KR1020027007536A patent/KR20020062334A/ko not_active Application Discontinuation
- 2000-12-20 JP JP2001549340A patent/JP2003519115A/ja not_active Withdrawn
- 2000-12-20 AT AT00990799T patent/ATE294773T1/de active
- 2000-12-20 US US10/149,449 patent/US6774136B2/en not_active Expired - Fee Related
- 2000-12-20 CZ CZ20022240A patent/CZ20022240A3/cs unknown
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- 2000-12-20 NZ NZ519976A patent/NZ519976A/en unknown
- 2000-12-20 PL PL00356523A patent/PL356523A1/xx unknown
- 2000-12-20 BR BR0016781-9A patent/BR0016781A/pt not_active Application Discontinuation
- 2000-12-20 HU HU0203732A patent/HUP0203732A3/hu unknown
- 2000-12-20 AU AU30147/01A patent/AU775709B2/en not_active Ceased
- 2000-12-20 PT PT00990799T patent/PT1246790E/pt unknown
- 2000-12-20 MX MXPA02005865A patent/MXPA02005865A/es active IP Right Grant
- 2000-12-20 DK DK00990799T patent/DK1246790T3/da active
- 2000-12-22 CO CO00097388A patent/CO5251380A1/es not_active Application Discontinuation
- 2000-12-26 PE PE2000001399A patent/PE20010986A1/es not_active Application Discontinuation
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2002
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- 2002-05-29 ZA ZA200204289A patent/ZA200204289B/en unknown
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-
2003
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Patent Citations (2)
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WO1996022276A1 (fr) * | 1995-01-20 | 1996-07-25 | Nippon Shinyaku Co., Ltd. | Derives d'ethylamine et medicaments |
EP0864559A1 (de) * | 1997-03-14 | 1998-09-16 | Grünenthal GmbH | Substituierte Aminoverbindungen und ihre Verwendung als analgetisch wirksame Substanzen |
Non-Patent Citations (2)
Title |
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CARDELLICCHIO C ET AL: "The Betti base: absolute configuration and routes to a family of related chiral nonracemic bases", TETRAHEDRON: ASYMMETRY,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 9, no. 20, 23 October 1998 (1998-10-23), pages 3667 - 3675, XP004141842, ISSN: 0957-4166 * |
DATABASE WPI Section Ch Week 199635, Derwent World Patents Index; Class B05, AN 1996-354450, XP002166569 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7964732B2 (en) | 2006-11-17 | 2011-06-21 | Pfizer Inc. | Substituted bicyclocarboxyamide compounds |
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